Genetic Variant BRAF:p.Gly32_Ala33dup (chr7-140924603-G-GCGGCGC) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001374258.1(BRAF):c.95_100dupGCGCCG(p.Gly32_Ala33dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,528,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A34A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

BRAF
NM_001374258.1 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 0.0760

Publications

1 publications found

Variant links:

Genes affected

BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]

BRAF Gene-Disease associations (from GenCC):

cardiofaciocutaneous syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
cardiofaciocutaneous syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
LEOPARD syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
Noonan syndrome 7
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
Noonan syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
anaplastic astrocytoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

BRAF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001374258.1

BP6

Variant 7-140924603-G-GCGGCGC is Benign according to our data. Variant chr7-140924603-G-GCGGCGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41448.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000284 (43/151504) while in subpopulation EAS AF = 0.000595 (3/5042). AF 95% confidence interval is 0.000242. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 43 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374258.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRAF	NM_001374258.1	MANE Plus Clinical	c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 20	NP_001361187.1
BRAF	NM_004333.6	MANE Select	c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 18	NP_004324.2
BRAF	NM_001374244.1		c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 19	NP_001361173.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRAF	ENST00000644969.2	MANE Plus Clinical	c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 20	ENSP00000496776.1
BRAF	ENST00000646891.2	MANE Select	c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 18	ENSP00000493543.1
BRAF	ENST00000288602.11	TSL:1	c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 19	ENSP00000288602.7

Frequencies

GnomAD3 genomes

AF:

0.000284

AC:

AN:

151504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000595

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000339

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000792

AC:

AN:

126314

AF XY:

0.0000578

show subpopulations

Gnomad AFR exome

AF:

0.000173

Gnomad AMR exome

AF:

0.0000415

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000978

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000856

Gnomad OTH exome

AF:

0.000510

GnomAD4 exome

AF:

0.000165

AC:

227

AN:

1377364

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

109

AN XY:

679562

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

31090

American (AMR)

AF:

0.000142

AC:

AN:

35332

Ashkenazi Jewish (ASJ)

AF:

0.0000400

AC:

AN:

25012

East Asian (EAS)

AF:

0.000197

AC:

AN:

35514

South Asian (SAS)

AF:

0.0000760

AC:

AN:

78980

European-Finnish (FIN)

AF:

0.0000299

AC:

AN:

33402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4150

European-Non Finnish (NFE)

AF:

0.000188

AC:

202

AN:

1076458

Other (OTH)

AF:

0.0000348

AC:

AN:

57426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000284

AC:

AN:

151504

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

73984

show subpopulations

African (AFR)

AF:

0.000387

AC:

AN:

41304

American (AMR)

AF:

0.0000656

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000595

AC:

AN:

5042

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000339

AC:

AN:

67770

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000146

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 11, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 33297573)

not specified

Benign:2

Feb 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRAF c.95_100dupGCGCCG (p.Gly32_Ala33dup) results in an in-frame duplication that is predicted to duplicate two amino acids into the encoded protein. The variant allele was found at a frequency of 0.00017 in 157184 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 37 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Cardiofaciocutaneous Syndrome phenotype (4.7e-06), strongly suggesting that the variant is benign. c.95_100dupGCGCCG has been reported in the literature in individuals affected with non-small cell lung cancer and hypertrophic cardiomyopathy as well as in one healthy individual (Shen_2019, Lin_2019, Micheu_2020). These reports do not provide unequivocal conclusions about association of the variant with Cardiofaciocutaneous Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Uncertain:1

Jun 06, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.95_100dupGCGCCG variant (also known as p.G32_A33dup), located in coding exon 1 of the BRAF gene, results from an in-frame duplication of GCGCCG at nucleotide positions 95 to 100. This results in the duplication of 2 extra residues (GA) between codons 32 and 33. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Micheu MM et al. Diagnostics (Basel), 2020 Dec;10:[ePub ahead of print]). This amino acid positions are highly conserved in available vertebrate species. In addition, this variant is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear.

RASopathy

Uncertain:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.95_100dup, results in the insertion of 2 amino acid(s) of the BRAF protein (p.Gly32_Ala33dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 33297573). ClinVar contains an entry for this variant (Variation ID: 41448). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

BRAF-related disorder

Benign:1

Jun 23, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Noonan syndrome

Benign:1

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Noonan syndrome and Noonan-related syndrome

Benign:1

Nov 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.076

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over